There are now known to be three human genes that code for the TPQ-containing amine oxidases, AOC1, AOC2, and AOC3.
AOC1 is the diamine oxidase found primarily in kidney (HKDAO), though it is also expressed in the liver and brain. The enzyme is thought to be involved in the catabolism of histamine and of putrescine and other polyamines, important mediators of nuclear events underlying cell proliferation. This suggests a fundamental role of HKDAO in the regulation of growth. At the same time, the H2O2 and aldehydes resulting from polyamine metabolism have been suggested to contribute to apoptotic cell death in brain injury. The presence of DAO at the interface between rapidly dividing (e.g., epithelial) and quiescent cells suggests that it might be involved in regulating cell division or differentiation at tissue boundaries. Involvement of DAO in the metabolism of histamine implicates its role in the progression of inflammation.
AOC2 is the retina-specific amine oxidase. The function is not yet clear, and there have been no suggestions in the prior art of a possible therapeutic effect of having a specific inhibitor of this enzyme.
AOC3 codes for an amine oxidase, which is also the human vascular adhesion protein (HVAP-1), responsible for the binding of lymphocytes to the endothelial cell surface and the promotion of their transendothelial migration. A number of studies point to this enzyme being a useful anti-inflammatory target. Further, since leukocyte migration from the blood to tissues is a prerequisite for normal immune responses, inhibitors of HVAP-1 will be important for modulating the immune response. This enzyme, responsible for the semicarbazide-sensitive amine oxidase (SSAO) activity in mammalian tissues, is largely associated with the plasma membrane of various tissues, and is particularly high in vascular and nonvascular smooth muscle cells, but is also found in other cell types such as adipocytes, chondrocytes, and odontoblasts. There are several pathological states where increased circulating SSAO activity has been found: diabetes mellitus, congestive heart failure, cerebral infarction, uremia, inflammatory liver diseases (e.g., cirrhosis), obesity, and hyperlipidemia. High levels of SSAO are also found in atherosclerotic plaques, and serum SSAO activity correlates with the severity of atherosclerosis, as well as intima-media thickness and serum cholesterol levels. It has been proposed that vascular SSAO is involved in the regulation of vascular tone, and thus vascular SSAO inhibition may offer a novel mechanism of vasodilation.
The role of SSAO in the pathophysiology of diabetes has been most extensively investigated. Elevated SSAO activity is associated with type 1 diabetes already at first clinical diagnosis, and in type 2 diabetes, particularly in diabetic patients with vascular complications, such as retinopathy and arteriosclerosis. It has therefore been speculated that SSAO may contribute to the development of vascular complications associated with diabetes. SSAO is associated with translocation of the glucose transporter GLUT4 into the adipose cell surface and thereby promotes glucose uptake in adipose tissue and smooth muscle cells. SSAO contributes to elevated formation of cytotoxic metabolites (principally methylglyoxal from aminoacetone, formaldehyde from methylamine, and H2O2 as by-product) that exacerbate advanced glycation of proteins (including crosslinking) and cause endothelial injury of blood vessels, resulting in early development of atherosclerosis and late-stage diabetic complications such as neuropathy, retinopathy, and nepropathy. Thus SSAO inhibitors may be ameliorative in the development of atherosclerosis and diabetic complications. Plasma SSAO activity is elevated in morbidly obese patients, which might contribute to the increased cardiovascular risk associated with obesity. A potent, selective SSAO inhibitor was found to reduce atherogenesis in a genetically obese diabetic mouse strain fed a high cholesterol diet. Furthermore, a recent study showed that an antibody to block VAP-1 in mice prevented diabetes in a subset of nonobese diabetic mice. Interestingly, aminoguanidine, which blocks advanced glycation and reduces nephropathy in animals, is more potent at inhibiting SSAO than its affect on glycation.
In addition to the LTQ-containing lysyl oxidase (LOX), human genes for four LOX-like proteins have been recently identified: LOXL, LOXL2, LOXL3 and LOXL4. In most tissues, LOX is responsible for the lysine-derived cross-links in collagen and elastin, which is the essential step for biogenesis and repair of the fibrillar extracellular matrix. Despite what should be a harmful effect of lysyl oxidase inhibition early in life, there is growing evidence that the enzyme also plays a role in late-onset fibrotic conditions in man.